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A new shot takes aim at a troublesome gene in the liver; it has been successful at permanently lowering "bad" cholesterol in mice.

Genome editing could be the future of cholesterol treatment. Researchers from the Harvard Stem Cell Institute and the University of Pennsylvania have developed a single injection that permanently reduces cholesterol levels in mice by altering their genes. If it is adapted for use in humans, it could decrease the risk of heart attacks by 40 to 90 percent.

Kiran Musunuru, Ph.D., an assistant professor in Harvard’s department of stem cell and regenerative biology, said it may take a decade to prepare the approach for human clinical trials. The study was published in Circulation Research, an American Heart Association journal.

Dr. Daniel J. Rader of Penn Medicine, who conducted the research in conjunction with Musunuru, said the therapy works by altering a liver gene called PCSK9.

In 2003, French scientists found that PCSK9 is a cholesterol regulator, and that rare mutations in the gene appear to be to blame for high cholesterol and heart attacks. These mutations are extremely rare and are limited to a few families worldwide.

In an exciting twist, researchers in Texas found that about 3 percent of people with the mutations experience the opposite effect: low-density lipoprotein (LDL) cholesterol levels about 15 to 28 percent below average.

Spreading a Beneficial Mutation

Musunuru and Rader aimed to turn normal PCSK9 genes into those with the latter “defect.” They used technology called CRISPR/Cas9, which makes it easier to edit the genome.

The PCSK9 gene is expressed mostly in the liver, where it generates a protein active in the bloodstream and prevents the removal of cholesterol from the blood. Several drug companies have been developing antibodies to fight PCSK9, Musunuru said, but people would need injections every few weeks.

Currently, many people use statin drugs, such as Lipitor, to lower cholesterol, but many taking the drugs still have heart attacks. “There is still a great need for other approaches,” Musunuru said in an interview with the Harvard Gazette.

“What we were thinking was that, with this genome-editing technology, we can do something we couldn’t do before: make permanent changes in the genome at the level of the DNA. So the question was whether we can use genome editing to make normal people like people born with the ‘good’ mutations.”

Musunuru said the team injected CRISPR/Cas9 into the liver, and most of the PCSK9 gene copies in the mice's liver cells were knocked out within three to four days. The researchers noticed a 35 to 40 percent reduction in cholesterol levels in these mice. That could translate into a reduction in heart attack risk of up to 90 percent in humans.

“The treatment would be most useful in patients with high cholesterol levels or who otherwise have a high risk of heart attack, since they would have the most to gain. But in principle the treatment should lower anybody's risk of heart attack,” Musunuru said to the Harvard Gazette.

A Vaccine for Heart Attacks?

Heart attacks are a leading natural killer worldwide, and one in two men and one in three women over the age of 40 will have a heart attack in their lifetime, Musunuru said. If the therapy proves safe for changing the human genome, it could be given like a one-time vaccination.

“We vaccinate against infectious diseases, not knowing who would otherwise get the disease, though we can make some guesses as to who is at highest risk and urge them to get the vaccination,” Musunuru said. “In the same way, we cannot be sure who will get a heart attack and who will not, and thus who would benefit most from the PCSK9 therapy.”

“That would be the rationale for giving it to the whole population, perhaps after reaching a certain age - say, 40 years old,” Musunuru added. “In a country like the U.S., where so many people suffer or die of heart attacks, giving the treatment to the whole population could save many lives.”